EORTC/MSG Consensus Revised definitions on fungal infection

Proven invasive fungal diseases

Deep tissue disease

Moulds[1]

Histopathologic, cytopathologic, or direct microscopic examination[2] of a needle aspiration or biopsy specimen showing hyphal forms with evidence of associated tissue damage (either microscopically or as an infiltrate or lesion by imaging)[3]

OR

Recovery of a mould by culture from a sample obtained by a sterile procedure from a normally sterile and clinically or radiologically abnormal site consistent with an infectious disease process, excluding BAL, cranial sinus cavity, and urine.

Yeasts

Histopathologic or cytopathologic examination² of a needle aspiration or biopsy specimen from a normally sterile site excluding mucous membranes showing yeast cells (Candida species may also show pseudohyphae or true hyphae)

OR

Recovery of a yeast by culture from a sample obtained by a sterile procedure (including a freshly (<24h) placed drain) from a normally sterile and clinically or radiologically abnormal site consistent with an infectious disease process,

Fungemia

Moulds

Blood culture that yields a mould e.g. Fusarium spp. in the context of a compatible infectious disease process[4].

Yeasts

Blood culture that yields yeast (e.g. Candida species) or yeast-like fungi (e.g. Trichosporon spp.)

Endemic fungal disease[5]

Disseminated and/or pulmonary[6] disease

Must be proven by recovery in culture from a specimen obtained from the affected site, in host with a temporally related illness consistent with a fungal infectious disease process;

OR

if culture is sterile or not obtained, histopathologic or direct microscopic demonstration of appropriate morphological forms is considered adequate for dimorphic fungi having truly distinctive appearance.[7]

OR

Positive blood culture

In the case of histoplasmosis a diagnosis of disseminated disease may be established by a positive Histoplasma antigen test[8] on CSF, urine or serum by EIA, or the presence of characteristic intracellular yeast forms in a peripheral blood smear or in bone marrow.

Or in the case of coccidioidomycosis a diagnosis of disseminated disease may be established by demonstration of coccidioidal antibody⁹ in CSF, or a 2-dilution rise measured in two consecutive blood samples tested concurrently in the setting of a temporally related infectious disease process.

Cryptococcosis

Probable invasive fungal disease

Defined by at least

a) one host criterion

AND

b) one clinical criterion

AND

c) one microbiological criterion

Possible invasive fungal disease[9]

Defined by at least

a) one host criterion

AND

b) one clinical criterion

BUT

c) no microbiological criterion

Host factors

Host factors are not synonymous with risk factors and are characteristics by which individuals predisposed to invasive fungal diseases can be recognized. They are intended primarily to apply to patients treated for malignant disease and to recipients of allogeneic hematopoietic stem cell and solid organ transplant. These host factors are also applicable to those receiving corticosteroids and other T-cell suppressants as well as those with primary immune deficiencies

1)   Recent history of neutropenia (< 0.5 x 10⁹/L {<500 neutrophils/mm³} for >10 days) temporally related to the onset of fungal disease or ongoing neutropenia

2)   Receipt of an allogeneic stem cell transplant

3)   Prolonged use of corticosteroids (excluding patients with ABPA) at an average minimum dose of 0.3 mg/kg/day prednisone equivalent for > 3 weeks

4)   Treatment with other recognized T-cell immune suppressants such as ciclosporin, TNF-a blockers, specific monoclonal antibodies alemtuzumab, nucleoside analogues during the past 90 days

5)   Inherited severe immunodeficiency (e.g., chronic granulomatous disease, severe combined immunodeficiency)

Clinical criteria

Must be consistent with the microbiological findings, if any, temporally related to current episode and other potential causes must have been eliminated

Lower respiratory tract fungal disease

A) the presence of one of the following “specific” imaging signs on CT:-

·         Well defined nodule(s) with or without a halo sign

·         Wedge-shaped infiltrate

·         Air crescent sign

·         Cavity

B) the presence of a new non-specific focal infiltrate

PLUS at least one of the following[10]:-

Pleural rub

Pleural pain

Hemoptysis

Tracheobronchitis

Tracheobronchial ulceration, nodule, pseudomembrane, plaque or eschar seen on bronchoscopy

Sinonasal infection

Imaging showing sinusitis

PLUS

at least one of the following:-

Acute localized Pain (including pain radiating to eye)

Nasal ulcer, black eschar

extension from the paranasal sinus across bony barriers, including into the orbit

Endophthalmitis

as determined by ophthalmologic examination

CNS infection

at least one of the following:-

Focal lesions on imaging

Meningeal enhancement on MRI or CT

Chronic disseminated candidiasis

Small, peripheral, target like abscesses (new nodular filling defects, bull’s-eye lesions) in liver and/or spleen

Microbiological Criteria

Cytology, direct microscopy or culture:

1.      sputum, BAL and bronchial brush samples demonstrating the presence of fungal elements either by recovery by culture of a mould (e.g. Aspergillus spp., Fusarium spp., Zygomycetes, Scedosporium spp.) or detection by cytology or direct microscopy of hyphal forms

2.      sinus aspirate: recovery by culture of moulds from or detection of hyphal forms by cytology or direct microscopy.

3.      Skin ulcers, draining soft tissue lesions or fissure for which both microscopy and culture are required

Detection of antigen, cell wall constituents or nucleic acid

4.    Galactomannan antigen EIA (Platelia).

a)      a single plasma or serum sample positive for galactomannan

b)      a single BAL, pleural fluid or CSF sample positive for galactomannan

6. Glucan Assay is primarily applicable for aspergillosis and candidiasis and does not detect Cryptococcus species nor the Zygomycetes (Rhizopus spp., Mucor spp. Absidia spp.)

a single serum sample positive for beta-D-glucan

7. Polymerase Chain Reaction to detect nucleic acid

Until a PCR system is developed that has been externally validated, a positive PCR result for blood, tissue, or BAL fluid for the specific fungus studied will not be considered microbiological evidence of invasive fungal disease.

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[1] Append identification at genus or species level from culture, if available.

[2] tissue and cells submitted for histopathology or cytopathology should be stained by Grocott-Gomorri methenamine silver stain or by periodic acid Schiff stains to facilitate inspection of fungal structures. Where possible, wet mounts of specimens from foci related to invasive fungal infectious disease should be stained with a fluorescent marker (e.g., calcofluor or Blancophor)

[3] Individual fungal invasive disease entities e.g. proven aspergillosis require culture and identification. Faiiling this the disease is designated as proven mould invasive fungal disease

[4] Other moulds can cause fungemia. However contamination should be excluded before assigning the diagnosis of proven invasive fungal disease

[5] Histoplasmosis, blastomycosis, coccidioidomycosis, and paracoccidioidomycosis, sporotrichosis and infection due to Penicillium marneffei

[6] the medical history must be established to distinguish between a primary and chronic pulmonary infection. Onset within 3 months defines a primary pulmonary infection.

[7] Histoplasma capsulatum variety capsulatum may resemble Candida glabrata or Leishmania in tissue but can be distinguished from them by the characteristic histologic features of granulomatous inflammation and staining by Grocott-Gomorri methenamine silver stain

[8] Testing should be performed only in laboratories where the assays have been validated; i.e., clinical correlations made with results and titers, and with data available on false positive and false negative rates with the test as performed in that laboratory.

[9] provided other plausible causes have been excluded

[10] symptoms not necessary if there is mycological evidence